Tuesday, December 30, 2008

As I liked to fancy myself as something of a 60s student radical, on becoming a medical student in the early 1970s I vowed not to join the AMA--mostly because that that time it stood squarely against any efforts to provide universal access to health care. More recently, some of my AMA member friends periodically try to persuade me that I could do more good as a critic inside rather than outside the organization and that I should join.

This is one of those times when I am very pleased not to be an AMA member.

Dr. Joseph M. Heyman, chair of the AMA Board of Trustees, has recently spouted off on the issue of selling physicians' prescribing info to the drug companies:

What apparently prompted this comment was the recent action of the US 1st Circuit Court of Appeals, reversing a lower court ruling that prevented implementation of the New Hampshire law that would ban the sale of physician prescribing information. Dr. Heyman personally has no trouble sharing his prescribing info with Pharma, but admits that some of his fellow docs see the issue differently. He therefore thunders against the court ruling, and the New Hampshire law, as threatening "physician choice."

The commentary is basically a long praise of the AMA's Physician Data Restriction Program, begun in 2006. The PDRP is supposed to allow any physician (AMA member or not) to opt out of the organization's current practice of selling identifiers.

Some background--Medical data mining firms currently buy prescription data from pharmacy chains, pharmacy benefit managers, and who knows what else. They take out all the patient identifying data to comply with privacy laws. They then sell this information to drug companies to allow them to carefully target their sales pitches to docs by letting the drug reps know exactly what and how many prescriptions that doc has recently written (for instance, does he prescribe a lot of your company's drug; or does he prescribe a lot of the competitor drug; and when asked by the rep what he prescribes does he tell the truth). These data, however, are useless unless you can turn the code number that identifies the doc who wrote the Rx into a name and address. That's where the AMA comes in-- they maintain a master file of all those code numbers and they sell that list to the data mining companies for many millions of bucks annually, making up a tidy portion of the AMA's annual revenue.

Till 2006, individual docs (besides having no clue that all this was happening behind their backs) had no say in whether the AMA sold their identifying information. With the start of the PDRP, the AMA quite grudingly offered the choice of opting out. Reports from neutral parties were that very few physicians exercised that right to opt out and most docs were unaware that the PDRP was available.

Why do I accuse Dr. Heyman of sleaze? Mainly because of this statement: "The AMA does not collect, license, sell or have access to physician prescribing data. Health care information companies collect and compile physician prescribing data and sell it to pharmaceutical firms. Through licensing agreements with these companies, the AMA can exert influence to offer programs such as PDRP."

This is a pretty slippery assertion. The impression it seems designed to leave with the reader is that the AMA does not profit from the sale of prescribing data and that it can influence the companies that do sell the data only indirectly; but the AMA is so influential that somehow the PDRP works and those companies agree to abide by the request not to release some individual docs' data. Which of course is not quite true. The truth is that the AMA does not directly sell the prescribing data, but they do sell the secret code that you need to understand the prescribing data, and they make a bundle off selling that. (There is a relevant scene in the Marx Brothers movie, A Day at the Races, but that would take me too far afield.) The PDRP works if it does because the AMA has direct control over the data that it does sell, not because it can "exert influence" over the data miners. (Or so all previous accounts from neutral sources have explained.)

Dr. Heyman refers his readers to the AMA's website that describes PDRP in more detail, and that website directs you in turn to a glitzy brochure:

The brochure (almost all photos and hardly any text) seems designed to persuade you of two things--one, physician choice is absolutely essential here and it would be an ethical outrage if that choice were ever taken away; and two, there are tremendous public health benefits to selling the prescribing data. The AMA further promises to launch a new information service to docs allowing them to compare their own prescibing practices to that of their peers. (Which important service you could of course not have access to, if you were so dim-witted as to have opted out via the PDRP.)

AMA critics point out that hardly any legitimate (that is, non-commercial) researcher uses these data as they are simply too expensive to purchase. I would add that in my last 10 years or so in practice, I had virtually all the data I could want on how my prescribing practices compared to other docs in my community through the kindly managed care plans that wanted me to keep my costs down.

I find it interesting that the AMA has elected to identify the sole ethical question related to this issue as physician's freedom of choice. The ethics of assisting the drug industry to make drugs more costly for patients by aggressively marketing physicians to prescribe only expensive brand-name drugs seems irrelevant to them--as does the ethics of the AMA itself profiting handsomely from this practice.

Tuesday, December 23, 2008

For those of you who are sick and tired of my posting about Dr. Charles Nemeroff and his misdeeds, good news--we may finally have reached the effective end of this saga. The quickest way to access the key documents is via Sen. Charles Grassley's website at the Senate Finance Committee:

Under the date "12-22-08" you will see three links, to a letter from Emory University; to a letter from Emory to the NIH; and to a comment by Grassley on both of the above.

Basically, Emory says that it has completed an initial investigation of Dr. Nemeroff and his unreported income from drug companies. The outcomes: He is to resign permanently as chair of Psychiatry; he is to be banned from any NIH study for two years; he is banned from accepting any money for speaking at events other than formal CME programs; and (according to the NIH letter) he is in a number of other ways being put on a very short leash and will be required to have the administration approve virtually his every move in relationship to accepting money or working with industry.

The Emory letter notes that Dr. Nemeroff believes that he was not required to report his speakers' fees under the then-existing Emory policy. He is quoted as expressing regret for his past actions and promising full cooperation with this new regime.

If things are as they appear then one of the most egregious flaunters of ethical propriety in the relationship between medicine and the pharmaceutical industry has at last been laid low.

It's pretty hard to tell from the articles exactly how widespread are the abuses described, as U.S. drug firms, seeking both cheaper and quicker trials of their new drugs to submit for FDA approval, abandon the US for countries like India--despite the fact that most Indians will never be able to afford the drugs that finally complete the trials. The impression given is that the problem is quite severe, because the system is largely unregulated and unsupervised. The FDA is only just now opening an office in India to allow it to do audits of ongoing trials. According to Hundley, bribery and corruption are so widespread at all levels of the Indian health care system, with doctors and hospitals so overextended that patients routinely feel obligated to pay bribes just to get the most basic care, that it is impossible to imagine that so-called ethics review is legitimate. There are numerous accounts of subjects being asked to sign consent forms in languages they cannot read.

One of Hundley's most interesting interviews is with Kamlesh Solanki, a Dalit (untouchable or lowest caste) who previously worked as a human guinea pig for drug trials. The best of these paid him $150, equal to nearly half a year's wages for a farmer in that region of India. He enjoyed luxurious quarters as a guinea pig with air conditioning, TV, and cushy mattresses on the bed. Despite these benefits he gave up the trial business when he came to realize how much more subjects were paid in the US, and after a subject died in a 2002 Phase I trial of an antidepressant. "Do they think we are worth less [than US citizens]?" he asked Hundley.

--Sen. Charles Grassley's (R-IA) campaign to expose corrupt practices at the medicine-pharma interface has netted an interesting internal document from Wyeth--analogous to some ghostwiting-related memos I discussed in HOOKED.

Grassley's team has unearthed a Wyeth memo detailing a campaign to sell its hormone combo Prempro, even after a major study revealed its association with increased breast cancer risk. The memo lists topics, titles, and outlines for a series of articles to be written by the staff of DesignWrite, a medical information company, with the goal of attracting putative academic "authors" for each article and then placing them in journals.

Grassley has demanded information from Wyeth and DesignWrite regarding the so-called authors and payments made to them. Wyeth denies that any of them received any money.

Reactions to this round of charges are interesting. Wyeth accuses Grassley of recycling outdated arguments, saying that besides not being paid, the academic "authors" had full editorial control over the final articles. This is of course the position of deniability that any drug firm can adopt with reference to ghostwriting. The putative author can, of course, exercise editorial control. Most are "too busy" and so elect not to, or to change only a few minor bits of language. Whistleblowers like David Healy have previously revealed how the attempt to actually exert serious editorial control quickly leads to the withdrawal of the invitation to be the "author" or to receive the opportunity in the future.

Of the two "authors" named by Wilson, one, Dr. John Eden, director of the Sydney Monopause Center in Australia, was purported author of an "Editor's Choice" feature in the May 2003 American Journal of Obstetrics and Gynecology, denying that "definitive evidence" existed tying Prempro to breast cancer. Dr. Eden refused any comment for the article. The documents state that the draft manuscript was written by DesignWrite. The journal says it is investigating.

The second named "author" is Dr. Lila E. Nachtigall, director of the Women's Wellness Center at NYU. Dr. Nachtigall denied to Wilson that anyone had written any of her 1000 articles or three books, and denied any recollection of being provided with a draft or outline. (She also suggested that the U.S. Senate had more important things to worry about than to come pestering her.)

My hope is that each of these instances will be investigated to the hilt, and that if any of these academics are found to have actually engaged in ghost-authoring, their respective institutions should make a severe example of them--a penalty notably absent from previous instances of this offense, despite the fact that all agree that ghostwriting is the most inexcusable of all ethical lapses related to Pharma.

Friday, December 19, 2008

I have been trying to follow the Nemeroff saga closely in this blog because it seems that Dr. Charles Nemeroff is a sort of poster child for the extreme versions of the (un)ethical issues I am trying to address here:

Emory told Sen. Grassley that as part of their promised investigation into why Nemeroff seemed to have stuffed his pockets with far more cash than he ever reported to Emory or to the NIH, they discovered that Dr. Nemeroff had not reported some income because it was for talks that he gave that were "CME-like." Presumably this was supposed to mean that the talks were educational and not promotional. Sen. Grassley shot back a 60-page letter noting that none of his legal staff could discover anywhere the term "CME-like" in any policies. He was so unkind as to suggest that maybe Emory made up this term out of whole cloth. He gently hinted that maybe Emory ought to review the legal penalties for making false statements to Congressional investigators.

As Emory and Grassley duke it out, a sidebar mention in the blog post caught my attention, and seems in many ways much more illustrative of the depths to which (some) physician behavor has sunk. WSJ blog had previously reported on a "Dear Me" letter that Nemeroff had written in 2000:

The story of the letter is this-- Nemeroff was then editor of the journal called Depression and Anxiety. I assume this to be a peer reviewed journal as it is indexed in PubMed. Nemeroff said in the "Dear Me" letter that he was paying himself $3000 to write an article for a special supplement the journal was putting out, to celebrate the 5th anniversary of the antidepressant drug Effexor. (Apparently this was a form letter to be sent to all authors of articles in the supplement, and so "Dear Me" was just Nemeroff's shorthard way of saying that he was one of the authors as well as the editor. Maybe the secretary was supposed to type in his name but forgot to.) The records available to the WSJ blog via the Grassley committee then show that Nemeroff cut himself a $3000 check out of a grant fund that the manufacturer of Effexor, Wyeth, had given to Emory.

Now we can talk all day about editorial conflicts of interest, about how Nemeroff as editor could first decide that there should be a special supplement in his journal that was basically nothing but an infomercial for a single drug, then decide in his editor role that he was one of the brilliant authors who should be asked to write an article, and then proceed to pay himself $3000 of company money for writing the article (assuming that it was not ghostwritten on his behalf by company hacks)--all the while failing to report in the journal that any of this was industry funded.

We could talk about all that, but I want to get back to basics here. Is not a medical journal supposed to be, in some distant sort of way, somehow about the science of medicine? About the scientific facts that physicians ought to know to take good care of patients? Do not the authors and editors of journals have some basic duty to promote the quality of medial science? If so, could somebody please explain to me what the bleep the fact that it's the 5th anniversary of a drug have to do with anything that could conceivably be of scientific interest? And how any self-respecting editor or academic physician could write, or any physician could read, an article "celebrating" the anniversary of the drug without puking? Regardless of who pays for it?

Please explain all this to me and then we can talk about conflicts of interest.

Tuesday, December 16, 2008

The e-mail lists have been abuzz with the latest allegations of pharmaceutically linked impropriety. I can't seem to get the full link to appear in this post for some reason (I am actually doing this from a hotel in Beijing--go figure) , but go to www.newsmax.com and search for "Nobel Prize bribery." The allegations are that AstraZeneca stands to gain a lot of sales for its human papillomavirus (HPV) vaccine as a result of the publicity of the discoverers of HPV winning the Nobel Prize, and so via a couple of intermediary PR organizations, it managed to exert financial influence over the prize committee. The Swedish authorities are investigating this as a possible criminal act, though according to the press account the Swedish media have been notably silent on the matter.

Among several good points Don makes is that the study was stopped early because of the supposed success of Crestor in preventing cardiovascular events--despite the very low absolute size of that "success." The early stoppage of trials is becoming a staple in industry-sponsored research, notes Light. The result is that the trial may not have gone on long enough to show the true side effect profile of this drug in an elderly population. If the Kentucky Derby were run like a modern clinical drug trial (if Light is correct about this), it would no longer be a mile-and-a-quarter race. Rather, the race would be declared over at whatever point the drug company's favored horse was ahead.

It's a pretty good bet that either of the two top names mentioned in the blog post, Joshua Sharfstein and Steven Nissen, would be seen as anathema by the drug industry. Therefore the battle over who gets named FDA head will be an excellent barometer of whether the new Congress and White House are positioned to rein in PhRMA power and influence, or whether it is going to be more of the same. (PhRMA hopes for more of the same, as they tilted heavily toward giving campaign contributions to Dems last year just to be prepared for this eventuality.)

The WSJ post mentions Janet Woodcock as a possible compromise interim head of FDA if the politics get nasty and a new permanent commissioner cannot be agreed on right away. I do not know any of these people and in private, Woodcock might be a wonderful person and eager to take the FDA in a new direction. Under the Bush administration, virtually every public statement Woodcock has made that I can recollect offhand has been as a pro-industry apologist. The history of PhRMA influence over legislation is that you seldom see a major debate on the floor of Congress over a measure. Instead, there is great hoopla over some reform (such as allowing imported drugs from Canada to lower prices). Then the measure is sent to committee. Then months and months go by and somehow, everything quietly disappears and it is as if the hoopla never happened. The influence PhRMA likes to wield is usually in the proverbial back room. So if the commissioner appointment seems somehow to disappear, and an interim commissioner stays on longer than was first planned, we'll know that things are working out as PhRMA wanted.

Monday, December 8, 2008

As part of my catch-up campaign I have to go back to another bit of news from last week. The Canadian Association of University Teachers (CAUT) again found it necessary to weigh in on the ongoing dispute between Dr. Nancy Olivieri and the drug firm Apotex:

Following that post (which offers a brief review of the Olivieri case, there being a longer description in HOOKED), I took a fair amount of heat from some Canadian colleagues who happen to be supporters of Dr. Olivieri. I don't expect to take any heat this time around, as according to CAUT, the behavior of Apotex is so egregious as to beggar description.

After a drawn-out legal battle in which Apotex accused Dr. Olivieri of badmouthing their drug, deferiprone, for thalassemia major, and Olivieri accused the company of trying to suppress data showing the drug's serious side effects, an agreement was reached in November 2004, in which each side agreed to stop disparaging the other. Apotex has now taken Olivieri back to court claiming that she violated the agreement.

CAUT has pointed out in its recent statement that Apotex has adopted a definition of "disparage" that seriously threatens academic freedom. According to some of the charges filed by Apotex with the court, Dr. Olivieri disparages them when:

she appears on a panel or gives a lecture to discuss the ethical issues of the relationship between medical research and the pharmaceutical industry, even if she never mentions Apotex or deferiprone by name

anyone else writes about the "Olivieri case" and mentions the charges against Apotex and deferiprone, even if Olivieri had nothing whatever to do with it (I presume according to Apotex, this post is an example of Dr. Olivieri disparaging them, even though she had and has no idea that I am writing this, and she and I have in fact never met or spoken)

I have no independent source besides CAUT to document Apotex's recent bad behavior. But unlike CAUT's earlier report on the Olivieri case, which drew criticism because many of the actors in the drama who disagreed with Olivieri refused to be interviewed by the CAUT investigators while Olivieri supporters all participated, the present statement seems based strictly on legal documents filed with the court. Assuming CAUT's allegations to be generally true, there is no question this time of different points of view among different participants in the case. This would appear to be a baldfaced attempt to muzzle a critic of the pharmaceutical industry.

After several weeks of not all that much happening at the Pharma-Medicine-Ethics interface, things have gotten busy again, to the extent that our fellow bloggers have even scooped us in some cases. Herewith I attempt to catch up.

--about the Cleveland Clinic's plans to create a new portion of their website in which all conflicts of interest of their staff physicians will be publicly reported. The University of Pennsylvania Medical Center reports a similar program. On the industry side, both Merck and Eli Lilly plan to start posting information on all their payments to physicians in 2009.

Abelson suggests that the media embarrassment suffered by large medical centers when previously undisclosed conflicts of interest are outed has led to this nascent movement, along with the investigative interest that Sen. Charles Grassley has shown in exposing high-rolling academic physicians who somehow have neglected to report their conflicts of interest. (See most recent post, http://brodyhooked.blogspot.com/2008/10/could-new-revelations-bring-down.html).

The Cleveland Clinic mentioned in passing that it expects that only a quarter of its physicians will have anything to report on the new website. HOOKED takes the position that disclosure of conflicts of interest is a relatively unsatisfactory substitute for getting rid of the conflicts in the first place. It remains to be seen whether physicians will be less likely to enter into conflicted relationships with industry when they know that the results will be publicly posted.

Turner and colleagues in Portland showed a truly scary degree of publication bias in journal articles about depression--with roughly half the research studies of SSRI antidepressants showing effectiveness and half not, and with virtually all studies that showed effectiveness getting published, and virtually none of those showing no effectiveness getting published. They managed this study by comparing the FDA biostatisticians' independent review of data presented as part of new drug applications, with the eventual publication that resulted (or failed to result) from the research. They also showed that many published studies were "spun" as positive when they had been assessed by the FDA experts as negative; and that the effect sizes reported in the published studies were frequently inflated from those discerned by the FDA review. The major limitation of Turner et al. was that they addressed only one class of drugs, antidepressants. They also included data that are now many years out of date, perhaps not reflecting more recent practices.

A group at UCSF led by Kristin Rising set out to remedy these deficiencies in a new study:

They looked at all new molecular entities approved by the FDA in the years 2001 and 2002, reasoning that this would have given the investigators enough time to publish all studies that were likely to be published. They reviewed the FDA assessments of all efficacy studies submitted by the drug companies as part of those new drug applications, conducting an extensive search to see if that study was ever published. They also compared the primary endpoints and the conclusions of all FDA-submitted studies with what appeared in the resulting publication (for those studies that were published).

The results were in the same general ballpark as what Turner et al. had found for antidepressants, only not quite so dramatically disastrous. Rising et al. found that 78 percent of the studies they looked at were published. A study submitted to the FDA that showed the company's drug to be effective was about 4 times more likely to be published. Between FDA submission and eventual journal publication, a number of primary trial endpoints that did not show the drug favorably got dropped out, and some new primary endpoints that had not been submitted to the FDA were added, in each case showing the drug in a positive light. The statistical significance of some outcomes changed between FDA submission and publication, in each case in a way that favored the drug.

In sum, Rising et al. noted the same shenanighans--multiple changes being made to the study results by the time they were published, if they were published at all, resulting in a drug footprint in the published literature that bore only a tenuous resemblance to the data submitted to the FDA. The basic lesson is that commercial sponsorship of pharmacotherapy trials has made it harder and harder to practice evidence-based medicine, as the "evidence" is routinely altered in such a way as to make drugs look more effective and safer than they are.

Rising et al. note that a number of the shenanighans they detected could have been prevented by the earlier adoption of mandatory trials registries, aso those who believe that this is the answer to commercial sponsorship will be heartened. I argue in HOOKED that registries are a useful first step but that ultimately a bigger firewall between company money and the conduct of clinical trials is needed.

I have objections, much of the time, to the media's present fetish with always including a "personal interest" anecdote in any news story about medicine. In this case, however, the personal angle is essential, so it's highly appropriate that Harris begins with the story of Bruce Hardy of Ruislip, UK, who has metastatic kidney cancer and who might get an average of 6 months' extra survival with Pfizer's new drug, Sutent--at a cost of $54,000.

NICE has decreed that as a general policy matter, Britain's publicly funded National Health Service cannot afford more than about $22,750 to prolong life for 6 months. (We assume that Mr. Hardy does not have the resources to go into Britain's private medical system where he could get whatever he wanted, so long as he paid for it himself or through private insurance.) After stormy protests NICE is reconsidering this policy.

Harris nicely (no pun intended) lays out the dilemma. According to NICE's detractors, this is heartless policymaking. How can you niggle over a few pounds with human lives hanging in the balance? According to NICE's defenders, the problem is not heartless bureaucrats deciding who lives and who dies, or how medicine is practiced--it is heartless drug companies that price their drugs out of reach. (Indeed, now that it's widely known what price limits NICE is willing to work within, drug companies have suddenly discovered that they can price their drugs for the British market lower than they used to.) You can read both sides of the story in this article.

As this blog is not about health policy generally and not about drug pricing, except as it bears on the ethics of medicine's relationship with the drug industry, I'll say no more about NICE, except to agree in passing with those who argue that the US is in deep doo-doo managing health care costs unless we somehow figure a politically viable way to invent our own version of NICE. All I want to comment for purposes of this blog is to note a small gap in Harris's otherwise comprehensive account. He describes the protests from angry oncologists and their patients that are forcing NICE to reconsider the limits they have set on cancer drugs. But he fails to follow the money trail to study how much drug company money is behind these protests. The industry is masterful in using patient advocacy organizations and other supposedly neutral bodies as PR fronts. Just as with the highly publicized controversy when NICE refused to pay for largely ineffective Alzheimer's drugs several years ago, I'd be willing to bet that the supposedly grass-roots protest was largely industry-funded "astroturf."

And, if you want to explore the ethics of NICE's approach to health care rationing, I must recommend the forthcoming book of my long-time colleague, Leonard Fleck of Michigan State University, Just Caring: Health Care Rationing and Democratic Deliberation, due out from Oxford University Press in March 2009.